The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants
The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants
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DOI：
10.1007/s12325-019-01198-9
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发表时间：
2019-12-20
影响因子：
3.8
通讯作者：
Pithavala, Yazdi K.
中科院分区：
文献类型：
--
作者：
Chen, Joseph;Xu, Huiping;Pithavala, Yazdi K.
劳拉替尼是第三代酪氨酸激酶抑制剂，获批用于治疗间变性淋巴瘤激酶（ALK）阳性的转移性非小细胞肺癌;细胞色素P450（CYP）3A在劳拉替尼的代谢中发挥重要作用。方法本项I期、开放标签、两阶段、交叉研究评估了口服利福平（一种强效CYP 3A诱导剂）对口服劳拉替尼（NCT 02804399）药代动力学和安全性的影响。健康受试者在第1阶段接受100 mg劳拉替尼单次给药，随后在第2阶段接受利福平600 mg/天（第1-12天）和100 mg劳拉替尼单次给药（第8天）。在每次劳拉替尼给药后120小时内采集血样。结果当在利福平每日给药期间给予单剂量劳拉替尼时，（阶段2），劳拉替尼外推至无穷大的血药浓度-时间曲线下面积（AUC（inf））和最大血药浓度（C-max）分别为14.74% [90%置信区间（CI）12.78%，17.01%]和23.88%（90% CI 21.58%，26.43%）。在第1阶段，劳拉替尼单次给药耐受性良好，但在第2阶段，劳拉替尼单次给药与持续利福平给药后1-3天内，在所有受试者中观察到转氨酶值升高（11例受试者为2-4级）。因此，停止利福平给药。转氨酶水平随后恢复正常（中位恢复时间：15天）。未观察到胆红素升高。结论：与单剂量劳拉替尼单独给药相比，在利福平每日给药基础上增加单剂量劳拉替尼可显著降低劳拉替尼血浆暴露量，并与所有健康受试者中严重但自限性的转氨酶升高相关。这些观察结果支持产品标签中的禁忌症，即劳拉替尼与所有强效CYP 3A诱导剂合并使用。
Introduction Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. Methods This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib. Results When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUC(inf)) and maximum plasma concentration (C-max) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed. Conclusions The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers.